Mary Gates Endowment For Students

Amanda Chen

Mary Gates Research Scholar, Winter 2022

Research Project: GHSR-1a Modulates Tumor-Induced Lipid Oxidation Independently of Ghrelin in Cachectic Mice

Project Description: Cachexia is a debilitating syndrome that accelerates muscle and fat wasting, affecting up to 80% of cancer patients with no current effective treatment. This condition is associated with weakness, fatigue, and poor tolerance to chemotherapy. Recently proposed as a therapeutic option due to its anabolic effects on preserving muscle and adipose tissue, ghrelin has been reported to attenuate Lewis Lung Carcinoma (LLC)-induced weight loss and lipolysis, also partially regulated by its only known receptor growth hormone secretagogue receptor (GHSR-1a). Tumor-induced lipolysis is associated with an alteration of substrate utilization. However, the extent to which these effects of ghrelin relate to substrate utilization (lipid oxidation and carbohydrate oxidation, LO and CHO) remains unclear.

This project seeks to determine if ghrelin’s effect on LO and COX in the LLC-induced cachexia model is dependent on GHSR-1a. Adult male C57BL/6J GHSR-1a knockout (KO) and wild-type (WT) mice were treated with or without LLC tumor, then injected with vehicle or ghrelin (0.8 mg/kg). Metabolic parameters were evaluated by the Comprehensive Lab Animal Monitoring System, in which I analyzed LO and CHO (calculated mean values and performed statistics). Tumor implantation led to an increase in LO and a decrease in CHO in tumor-bearing mice. GHSR-1a KO mice had a greater increase in LO compared to WT, highlighting the receptor’s essential role in maintaining normal levels of LO during cachexia, with no genotype effect for COX. Ghrelin did not prevent the LLC-induced response regardless of GHSR-1a expression, hence its mitigating effects for lipolysis in cachexia are not dependent on the regulation of LO or CHO. In conclusion, GHSR-1a plays a role in modulating LO in tumor-induced cachexia, and these effects are independent of ghrelin. More studies are needed to further characterize the pathways involved, including alternative receptors of ghrelin or its adjacent mechanisms.

What have you learned throughout your research project?

This project helped me shape my interest in molecular biology. Although metabolism was an area I wasn’t familiar with initially, it really tied in the academic knowledge in compact experiments, allowing me to deepen my scope of understanding in cell functioning. The research itself is an incredible experience that I couldn’t have gained elsewhere.

What piece of advice do you have for future applicants?

Make use of the resources available provided by school, whether it be the great mentors and peers, opportunities and equipment. Most importantly, enjoy exploring as the project goes.